The overall goal of this program project is to understand the immunopathogenesis of insulin-dependent diabetes mellitus (IDDM) at the cellular and molecular level. The program involves a collaborative interaction between members of four departments organized into projects supported by four core facilities. Expertise in immunology, molecular biology, cell biology and clinical and experimental studies of diabetes will be focused on the problem of the primary lesion in IDDM, the destruction of the pancreatic beta cell. The role of T lymphocytes, of cytokins, and of MHC molecules in this process will be analyzed, using a wide range of techniques. Specifically, we will address the following questions: What analyzed, using a wide range of techniques. Specifically, we will address the following questions: What are the autoantigens recognized by T cells on the beta cell? What receptors are involved in this recognition event? What regulates the activation of autoreactive T cells? How are the beta cells destroyed? What role do inflammatory cytokins play in the inductive and effector phases of beta cell destruction? What role does glucose metabolism play in susceptibility of beta cells to autoimmune attack? These questions will be addressed by collaborative interactions between the principal investigators of the four projects, which are as follows: Project 1, C. Janeway, PI: Using cloned, diabetogenic T cell lines, the nature of the T cell receptors and their beta cell ligands will be determined, and the role of beta cells in stimulating autoimmunity determined. Project 2, A. Hayday, PI: The nature of the T cell receptor genes involved in autoimmune diabetes and their impact on T cell receptor transgenic mice will be determined. Project 3: R. Flavell, PI: The effect of MHC and cytokine genes under rat insulin promoter on beta cell function and induction of autoimmunity will be determined. Project 4: R. Sherwin, PI. The mechanisms of beta cell destruction by T cells and the influence of glucose on beta cell susceptibility to autoimmune attack and induction of response will be determined. These four projects will be supported by an administrative core to coordinate the project as a whole, a NOD mouse colony critical to the in vivo experimentation in most projects, a laboratory for rodent islet isolation essential to most of the studies, and an immunocytochemistry facility to allow us to accurately assess immunopathology of beta cell destruction in vivo and vitro. The program is coordinate by frequent meetings of the program faculty, bridging the various departments.